Esters and thioesters of penicillin and their production



United States Patent TC ESTERS AND THIOESTERS F PENICILLIN AND THEIR PRODUCTION Erling Juhl Nielsen, Charlottenlund, and Rudolf Reiter, Herlev, Denmark, assignors to Lovens Kemiske Fabrik ved A. Kongsted, Copenhagen, Denmark No Drawing. Application July 7, 1954 Serial No. 445,884

Claims priority, application Denmark August 20, 1953 7 Claims. 01. also-239.1

This invention relates to novel esters and thioesters of penicillin and to their production.

It is known that esters of penicillin with certain aminoalcohols have a therapeutic efiect, particularly when used assoluble or dlfiicultly soluble salts with appropriate oramples of acids forming sparingly soluble salts with these basic esters are f. inst. hydrogen iodide and sulphanilic acid.

One object of the present invention is to provide novel penicillin compounds, which possess advantageous antibiotic properties,

vention is given together with results of biological testingof the compounds of the invention, and, further, the invention is illustrated by examples showing a convenient and used as salts with acids innocuous to human beings. Examples of suitable acids for use in forming salts with the present esters are: hydrochloric, hydrobromic and benzene sulphonic acid, toluenesulphonic acid and penicillin.

oils or amorphous powders, although they may in some phous.

The compounds of the invention are esters of penicillin with phenols and thiophenols having a basic substituent, said esters being represented by the formula:

where Z is from the class consisting of PenCOO and PenCOS, PenCO representing penicillin with hydroxyl removed from the carboxyl group; where Z is from the class consisting of hydrogen and the groups represented by Z where Y is from the class consisting of alkylene Although in many instances soluble Patented Dec. 23, 1958 groups and alkylene groups linked to a carbon atom in the phenyl ring through a member of the class consisting S-, NH, NR, RO, -RS,

chain, the total number of carbon atoms in Y not eX- ceeding 12, are of greater therapeutic value as compared with other compounds of the invention.

Thus, the group Y can be a methylene, an ethylene, a propylene or a butylene group, which may be substituted at one or more carbon atoms, if desired, with lower alkyl groups, such as methyl, ethyl or propyl.

Particularly good results in respect of lung accumulation have been obtained with compounds in which the Y esters of: p-diethylaminoethoxyphenol, p-hydroxybenzoic acid-diethylaminoethyl ester, p-hydroxybenzoic acid-diethylaminoethylamide, N (p hydroxyphenyl) N (diethyl) ethylenediamine, p (N 13 diethylaminoacetyl)-aminophenol and the corresponding thioanisoles, thioesters and thiamides.

The linkage of the penicillin group to the phenyl ring may be in any of the ortho, meta and para positions. However, 1t appears that compounds, in which the peni position, are of superior therapeutical value.

The R and R groups are preferably methyl or ethyl groups or groups which together with the nitrogen atom form a piperidine radical.

scribed hereinbefore, which method comprises reacting a phenol or thiophenol of the formula:

where V is hydroxyl or sulphydryl, and V is hydrogen, hydroxyl or sulphydryl, and where Y, R and R have the above named significance, with penicillin anhydride 3 01 another reactive penicillin derivative. The reaction can he carried .out in solution in .an inert solvent in which both reactants are soluble- However, the reaction can also be carried out by addingthe solid penicillin derivative 10 .a solution .of the phenol or 'thiophenol in an inert mixture or they may be isolated as their acid addition salts with one .of the above-mentioned acids innocuous .to human beings. If the esters themselves areto be isolated, the reaction mixture may for example be washed with an aqueous solution of sodium bicarbonate and water, and The solvent may then be evaporated When a salt is desired, a solution of the acid in question is added to the washed and dried reaction mixture, and the salt is then precipi- A number of biological tests were carried out with In the following Table 1, figures are given illustrating the penicillin levels in the blood, lung, liver kidney and spleen of guinea pigs one The figures represent international units of penicillin and a comparison is made between compounds of the invention and the Penicillin level in- .solvent or .the solid phenol -or :thiophenol to a solution 5 dried over MgSO .of-the pencillinderivative. in vacuum, leaving the ester.

The production of penicillin anhydride being diflicult and involving great losses, we prefer to use as a reactive penicillin derivative 21 mixed anhydride of penicillin and tated. a lower aliphatic monocarboxylic acid or an aromatic carhoxylic .acid, .such asbenzoic acid, or still more approthe compounds of the invention. .priate, a mixed anhydride of penicillin and a monoester of carbonic acid. Such mixed anhydrides are easily produced by reacting a penicillin salt with a chlorocarand two hours after subcutaneous injection. :bonic acid ester zinan inert solvent. Any stable salt of penicillin may be used, but we prefer to use penicillin salts with tertiary amines, such as the triethylamine or sodium and procaine salts of penicillin.

TABLE 1 Derivative oi benzylpenlcillin M- Hours Blood, Lung, Liver, Kidney, Spleen, Dose after I. U. I. U. I. U. I. U. I. U. inj. per cc. per g. per g. per g. per g.

Sodium salt Procaine salt i-(fl-diethylamlnoethyl) -pheny1 ester-citrate. i-(fipiperidinoethyl)-phenyl ester-hydrochlori e.

4-(fi-diethylaminoethoxy)-phenyl este s-(w-diethylaminoaceto)-phenyl ester-hydrobromide.

4-(N methyl -N diethylaminoethyl) -phenyl ester-dihydrochloride.

4 (5 diethylaminoethylthio carbarnldo) phenyl estencitrate.

4-(fl-diethylaminoethylearb-oxamido) phenyl ester-citrate 4-(w-dlethylarninoace hydrochloride S-(Q-diethyIaminQacetam hydrochlorid l-(h-diethylaminop pyl)-phcnyl 3-(fl-dlethylaminoethyl)-phenyl ester-citrate...

l a a 5-3% -5? 3? .21 a it a a s s is l a s a i 5-2-1-2? -1? 1? -21 l at a a l a, l 212 a a a l a a a a t l 3.13 s a r; l a i it 33 iii it l a s\ a N-ethylpiperidine salt, or with metals, such as the sodium or potassium salt.

The solvents used in the process do not necessarily have .to be such in which the reactants are soluble. In fact, we often use solvents in which one of the reactants is insoluble. By way of example, we may use methylene chloride, chloroform, ethyl acetate, acetone, ether, dioxan or tetrahydrofuran, single or mixed, and in the case of water-miscible solvents we may use aqueous solvents, when the latter are used, however, the water content should not exceed Such solvents are also suitable, when the mixed anhydride is reacted with the phenol or thiophenol and .it is generally preferred to carry out this second reaction in direct continuation of the production ofthemixed anhydride without isolating the latter.

The process of the invention is preferably carried out atlow temperatures within the range of from -20 C. to C. and .a convenient and suitable temperature is approximately 0 C.

The production of the esters is best carried out in the presence of a basic catalyst. Thus, if a metal salt of penicillin is used, we prefer to add a small amount of an organic base, for instance triethylarnine or pyridine, to the reaction mixture. vFor instance we may use 0.01 to 0.02% .of pyridine -(w./v.).

The esters may be isolated as such from the reaction In a further experiment the protracted effect of one of the compounds of the invention, the citrate of benzylpenicillin-4-(fl-diethylaminoethyl)phenyl ester (1 in Table 2), was compared with that of benzylpenicillin-diethyl aminoethyl ester-hydriodide (II), of the sodium salt of benzylpenicillin (III) and of the procaine salt (IV). These substances were injected subcutaneously in guinea pigs in doses of 50,000 I. U. per animal, and the penicillin level in the blood and lungs was determined at intervals after the injection. The results are given in Table 2. where the figures represent I. U. per cc. of blood and per g. of lung.

TABLE 2 I II III IV Blood Lung Blood Lung Blood Lung Blood Lung sodium salt of penicillin, blood (I. U. per cc.) and lungs (I. U. per g.) were determined 2 hours after the injection together with the distribution between free penicillin and penicillin ester. The results are given in Table 3.

TABLE 3 .ah

Blood Lung Compound 1 Total Peni- Free Total Peni- Free penicillln penipenieillin penieillin ester cillin cillin ester cillin 7 4.8 0.6 4.0 71 7.3 51 II 7.2 3.7 4.6 8.0 3.0 2.8 Sodium salt 4. 3 4.3 1. 8 1.8

Further, the sensitivity of a number of bacteria strains to the sodium salt of penicillin and to the above compound I of the invention was determined in dilution series.

Due to the slow liberation of free penicillin from compound I it was to be expected when using this tech nique that sodium penicillinate would have about twice the activity of most of the experiments. However, it was found that penicillin-resistant, penicillinase-producing strains Micrococcus pyogenes v. aureus were more sensitive to compound I than to sodium penicillinate.

The microorganisms were all highly virulent resistant from patients. The figures in Table 4 give the concentration of i which gives 50% inhibition.

TABLE 4 a N R Penicillin concentration Strain N 0.

Sodium Compound salt I 0.1 (non resistant) 0.03 0.06 OJ 5 (resistant) 185 36 CI 6 (resistant) 185 24 CI 7 (resistant) 185 48 CJ' (resistant) 16 8 OJ 9 (resistant)... 250 185 OJ 10 (resistant) 8 6 CI 11'(resistant) 62 Example 1 18.6 g. mole) of the cillin-are suspended in 100-ccs. of methylene chloride potassium salt of benzylpeni- 4.8 ccs. of ethyl chlorocarbonate mole). cooled in ice and 2 ccs. of a 1% solu- 'The standing with stirring for minutes. a solution of 9.65 g. of 4-(fi-diethylaminoethyl)- phenol in 40 ccs. of methylene chloride is added in one the methylene chloride is evaporated in vacuum. Then, a further 5.25 g. of citric acid-monohydrate in 100 ccs. of butanol are added, precipitating 28-29 g. of benzylpenicillin-4-(B-diethylaminoethyl)phenyl ester-citrate with a purity of 100% and a melting point of 80 C. (dec.). (a) =+136 C. (c.=2.5% in water).

In the above example ethyl chlorocarbonate may be replaced by the equivalent amount of other acid chlorides as specified below, whereby the specified yields of benzyl- Example 2 18.6 g. of the potassium salt of benzylpenicillin are suspended in ccs. of methylene chloride containing 4.8 ccs. of ethyl chlorocarbonate. The mixture is cooled in ice and 2 ccs. of a 1% solution of pyridine in methylene chloride are added. After stirring for 30 minutes, 9.65 g. of 4-(fi-diethylaminoethyl)phenol are added. After further 30 minutes, the reaction mixture is washed with bicarbonate solution, whereafter phase is dried over magnesium Methylene chloride is evaporated and the mother liquor may further yield 2.6 g., making a total of 22.7 g. of benzylpenicillin-4- (,B-diethylaminoethyl) phenyl ester-lactate, corresponding to 75% of the theoretical yield. The purity is 100% and (oz) =+168 (c,=2% in water).

If methylene chloride is replaced by trichlorethylene and ethyl chlorocarbonate by the equivalent amount of benzoyl chloride in the above example, benzylpenicillin- 4-(,8-diethylaminoethyl)phenyl ester-lactate is obtained in a yield of 60% of the theoretical.

If the potassium salt of the above example is replaced by 17.8 g. of the Example 3 18.6 g. of the potassium salt of benzylpenicillin are suspended in 100 ccs. methylisobutylketone. The suspension is cooled to 0 C., and 4.8 ccs. of ethyl chlorocarbonate and then 2 ccs. of a 1% solution of pyridine in methylisobutylketone are added. The mixture is left are added. After standing at 0 C. for 2 hours, 19.6 g. of benzylpenicillin-4-(,o-diethylarninoethyl)phenyl ester-lactate, corresponding to 65% of the theoretical, are filtered off.

By replacing ethyl chlorocarbonate with the equivalent amount of benzoyl chloride in the above example, a yield of 16.5 g. of benzylpenicillin-4-(,B-diethylaminoeth yl)phenyl ester-lactate is obtained, correspondingto 55% of the theoretical.

' added.

are dissolved in 100 ccs. of

C., whereafter 0.96 ccs. of ethyl 7 Example 4 p 3.72 g. of the potassium salt of penicillin are suspended in 75 ccs. of methylene chloride, and 0.96 ccs. of ethyl chlorocarbonate in 20 ccs. of methylene chloride are The mixture is cooled to C., and 0.02 g. of pyridine in 2 ccs. of methylene chloride are added. After stirring for 30 minutes, a solution of 2.9 g. of 4-y-diethylamino propyl)-phenol-hydrobrornide and 1.40 ccs. of triethylamine in 50 ccs. of methylene chloride is added. After standing at 0 C. for 2 hours the solution is washed with a saturated solution of sodium bicarbonate and water, whereafter the methylene chloride phase is dried over MgSO After removal of MgSO by filtration, acid-monohydrate dissolved in 20 ccs. of acetone are added. On addition of 100 ccs. of ether benzylpenicillin-4-(a-diethyllaminopropyl)phenyl ester-citrate crystallizes. The yield is 70% having purity corresponding to 755 I. U./mg. and the melting point is 95 C. (dec.).

In analogous manner 'b'enzylpenicillin-4-(B-diethyh aminopropyhphenyl ester-citrate is produced from 4-(13- diethylaminopropyl phenol-hydrobromide as an amorphous powder with a purity of 654 I. Ujmg.

From 2.72 g. of 3-tfi-diethylaminoethyl)phenol-hydrobromide the citrate of benzylpenicillin-3-(fi-diethylaminoethyl)phenyl ester is obtained as a white crystalline substance with a purity of 664 l.U./rng. and a melting point of 89-91 C. (dec.) in a yield of 65% of the theoretical. I

From 2.72 g. of Z-(B-diethylaminoethyl)phenol-hydrobromide, the citrate of benzylpenicillin-2-(B-diethylarninoethyl)phenyl ester is obtained as an amorphous powder. This is dissolved in water and the hydrobromide is precipitated on addition of an aqueous solution of potassium bromide. The aqueous phase is decanted, the precipitated viscous oil is dissolved in 75 cos. of methylene chloride and the solution is dried over MgSO After filtration, 200 cos. of ether are added whereby benzylpenicillin-2-(B-diethylaminoethyl)phenyl ester-hydrobromide is precipitated as an amorphous light-yellow powder in a purity of 694 I. U./ mg. the yield being 35%.

Analogous 4-hydroxy-w-diethylaminnoacetophenonehydrochloride yields benzylpenicillinl-(-w-diethylarninoacctophenyl ester-hydrobrornide in a purity of 950 l. U./ mg.

Example 5 4.46 g. of the N-ethylpiperidine salt of benzylpenicillin methylene chloride, and the solution is cooled to 0 chlorocarbonate are added. After standing at 0 C. for 30 minutes, a solution of 2.6 g. 4-hydroXy-w-diethylarninoacetanilide-hydrochloride and 1.4 ccs. of triethylamine in 50 ccs. of methylene chloride is added. After standing for 1 hour at 0 C. the mixture is left standing overnight at room temperature. The solution is then washed with a saturated solution of sodium bicarbonate and water and dried over MgSO The latter is filtered off and 2.1 g. of citric acid-monohydrate in ccs. of acetone are added. 0n addition of ether, benZylpenicillin-4-(w-di- 50 ccs. of isopropanol and 2.1 g. of citric ethylaminoacetamino pheuyl ester-citrate is precipitated as an amphorous powder. This amorphous citrate has a purity of 662 l. U./rng. and the yield is of the theoretical. y

In analogous manner 2.72 g. of N-diethylarninoethyl- 4-hydroxybenzamide-hydrochloride gives benzylpenicillin- 4-(w-diethylaminoethyl-carboxyamido)phenyl ester-citrate in a yield of 30% and with a purityof I. U./mg.

Example 6 to 0 C., and 0.02 g. of pyridine in 2 ccs. of methylene chloride are added. The mixture is left standing with stirring at0 C. for 30 minutes, whereafter a solution of 3 .4 g; of 4- (N-methyl-N-diethylaminoethyl) aminophenol-hydrochloride-hydrobromide and 2.8 ccs. of triethylamine in 100 ccs. of methylene chloride is added. The mixture is left at 0 C. for 2 hours, whereafter it is washed with sodium bicarbonate solution and water. After drying over MgSO the equivalent amount of an ethanolic solution of hydrogen chloride is added. The resulting solution is precipitated with 200 ccs. of ether, and the precipitated dihydrochloride is reprecipitated from ethanol-ether, whereby benzylpenicillini-(N-methyl-N diethylaminoethyl aminophenyl ester-dihydrochloride is obtained as an amorphous powder. The purity is 915 l. U./mg. and the yield is of the theoretical.

Example 7 3.72 g. of the potassium salt of benzylpenicillin are suspended in cos. of methylene chloride. Then 0.96 cc. of ethyl chlorocarbonate dissolved in 20 ccs. of -methylene chloride are added. The mixture is cooled to 0 C., and 0.02 g. of pyridine in 2 ccs. of methylene chloride are added, whereafter the mixture is left standing with stirring at 0 C. for 30 minutes. Then 2.22 g. A mole) of Z-hydroxy-w-diethylarninoacetanilide are added, and the mixture is left standing with stirring for 4 hours. After washing with sodium bicarbonate solution and ter, the solution is dried over MgSO Then, 2.1 g. of citric acid-monohydr'ate dissolved in 20 ccs. of acetone are added, whereafter the amorphous citrate is precipitated by addition of ether. The citrate is filtered olf and dissolved in water, and the amorphous hydrobromide is precipitated by addition of a surplus of an aqueous potassiurn bromide solution. The water is decanted off, and the hydrobromide is dissolved in 50 ccs. of methylene chloride. The solution is dried over MgSO. and the precipitated with ether. Thereby benzylpenici1lin-2-(w-diethylaminoacetarnino)phenyl ester-hydrobrornide is obtained as an amorphous powder. The purity is 930 I. U./mg.

Example 8 3.72 g. of the potassium salt of benzylpenicillin'ar'e suspended in 75 ccs. of methylene chloride, and 0.96 cc. of ethyl chlorocarbonate in 20 ccs. of methylene chloride are added. The mixture is cooled to 0 C., and 0.02 g. of pyridine in 2 ccs. of methylene chloride are added. After stirring for 30 minutes, 2.22 g. of 3-hydroxy-w-diethylaminoacetanilide are added. The mixture is left standing for 3 hours with stirring and then washed with sodium bicarbonate solution and water. After drying with MgSO the equivalent amount of ethanolic hydrogen chloride is added. On addition of ether, an amorphous hydrochloride is precipitated which is then re-precipitated from ethanol-ether. Thereby, benzylpenicillin 3 (w diethylarninoacetamino)phenyl ester-hydrochloride is obtained as an amorphous powder with a purity of 1060 I. U./mg.

In an analogous manner 2.52 g. of N-diethylarninoethyl-4-hydroxythiobenzamide gives benzylpenicillint- (N-diethylaminoethylthiocarbamido)phenyl ester-hydrodrochl'oride as an amorphous yellowish powder with a purity of 937 I. U./mg.

Example 9 1.86 g. 5 mole) of the potassium salt of benzylpenicillin are dissolved in 45 ccs. of methylene chloride, and- 0.48 cc. of ethyl chlor'ocarbonate dissolved in 5 ccs. of methylene chloride are added. After cooling to 0' C., 1 cc. of pyridine in methylene chloride (1%) is added. After stirring for 30 minutes, 1.025 g. of 4- (B-piperidinoethyl)pheitol dissolved in ccs. of acetone are added. After 'a reaction .period of /2 hour, the reaction mixture is washed with sodium bicarbonate solution and water and dried over MgSO After filtration,;,the solution is evaporated in vacuum, and the residue is dissolved ethanolic hydrogen chloride.

zylpenicillin 4 chloride crystallizes pointis 163-167 In an analogous pholinoethyl) phenyl melting point 166-7 0.02 mole of ethylcarbonic acid 1.95 g. (0.01 mole C. and the purity 10 10 in isopropanol and titrated with suspended in 25 tics. of methylene chloride are added,

I On addition of ether, benand the mixture is left at C. for 2 hours with stirring in a yield of 0.62 g. The melting 87 I. U./mg.

manner benzylpenicillin-4-(fi-morester-hydrochloride is obtained with 3 C. and purity 1055 I. U./mg.

Example 10 Example 14 the mixed anhydride of penicillin and are prepared in the usual manner. of -diethylaminomethylresorcinol 75 and then overnight at the After tained. On re-precipitatiou from methanol-ether, the To a q h e 0f roo mole of t lhlXed anhydflde 9 hydrochloride is obtained as an amorphous powder with benzylpemcillm and ethylcarbomc acld, prepared as m a purity of 7 L U,

2 g. of 4-(fl-dimethylaminoethyl)phenol dissolved 1n 25 ccs. of acetone are added. After two Example 15 the methylene chloride solution is washed with 15 8.72 g. (0.02 mole) of the triethylamine salt of ben- 21 solutlon of sodlum bicarbonate and with water and zylpenicillin are dissolved in 100 ccs. of methylene chlo- After filtration, the solution is ride, whereafter the solution is cooled to 0 C. 2.4 ccs and the residue is dissolved in (0.025 mole) of ethyl chlorocarbonate are added and er the calculated amount of citric the mixture is left at 0 C. for /2 hour.

acid dissolved in acetone is added. Thereby, 15 g. of 2.90 g. (0.01 mole) of 4-diethylaminomethylresorcinolbenzylpenicillin-4-(B-dimethylaminoethyDphenyl esterhydrochloride and 3.5 ccs (0.025 mole) of triethylamlne citrate crystallizes. By re-crystallization from ethanolare dissolved 1n 30 ccs of methylene chloride, the soluether 0.82 g. of crystals with a purity of 718 I. U./mg. tion iscooled to 0 C. and added tothe above described are obtained. solution The mixture is left at room temperature for Example 11 3 hours and then washed with water, sodium bicarbonate solution and Water and dried over MgSO After evapog g a gg ff g g g i gggg g z fifgg fi g ration in vacuum, the residue is extracted with ether, the ample 9 whereafter 2 49 g of 4 (p dibutylaminoethyn ethereal extrz tlclt1 1s filered1 313d the filtrate isdezfizporated to a s ru is 1s ISSO ve in acetone, an e ca cuphenol dlssolved m 32 of methylene chloride are lated Zm unt of a 05 molar solution of citric acid in added. After 1 hour, the methylene chloride solution t add d Th a O hous citrate 18 recl- Hated is washed and dried as described in the preceding exone i t 3 2. t th p It P b ample After evaporation 1n vacuum the residue is dlson z z gi ggfisg i solved in 50 ccs. of isopropanol, and the solution is i g i 1a m p y titrated with a solution of sulphuric acid in isopropanol. 35 Ex 16 On precipitation with ether, 1.97 g. of benzylpenicillinamp. 4- (B-dibutylaminoethyl)phenyl ester-sulphate are ob- T0 9 gf h i hy m salt of hellzylpehieilhn tained as an amorphous yellow powder with a purity of dissolved in 20 663 Of chloroform, a S0llltl011 0f 2 COS Of 710 I, UJm ethyl chlorocarbonate in 20 ccs of chloroform is added Exam le 12 40 at 0 C After standing for 10 minutes, a solution of p 3.6 g. of p-(B-diethylaminoethyl)phenol in 20 ccs. of To loo mole of the mixed anhydride of benzylpenicilchloroform is added whereafter the. mixture is placed lit; and ethylcarbonic acid in methylene chloride are overnight 'at 0 C. After washing with water, sodium added 895 g. of 4-diethylaminoethylphenol dissolved bicarbonate solution and again with Water the chloroin 30 ccs. of methylene chloride. After 1 hour, the calorm phase is dried over magnesium sulphate and then culated amount of citric acid dis olved in acetone is evaporated 1n vacuum. The residue 1s dissolved 1n added. On addition of ether, 1.7 g. of benzylpenicilccs of acetone whereafter 4 g of cltnc acid dissolved in lin-4-diethylaminoethylphenyl ester-citrate with a purity 40 ccs. of acetone are added I Thereby t e crystallin of 437 I. U./mg. are precipitated. The citrate is disbenzylpenicillin-4-(,d-diethylaminoethyl)phenyl ester-cisolved in water, andthe sparingly soluble hydriodide is trate is .obtamed and after recrystallization from 50 ccs precipitated by addition of an aqueous solution of po- 50 ethanol, the Yield 18 8 g The Purity of the substance tassium iodide. The precipitate is stirred with ethanols 710 gand the substance is decomposed 011 ether, whereby 0.8 g of amorphous benzylpenicillin-4- heating to about 0 C- diethylaminoethylphenyl ester-hydriodide are obtalned having a purity of 724 I. U./mg. Example 17 To a solution of 21.75 g. of the triethylamme salt of Example 13 benzylpenicillin in 50 cos. of chloroform a solution of 0.02 mole of the mixed anhydride of penicillin and 5 43 g 0f ethyl ehlol'oeal'hohate 111 0 8 Of Chloroethylcarbouic acid are prepared as described in the pro form l's added at After standing for 10 minutes, a vious examples. A solution of 0.01 mole of 3.5-dihysolution of of pus-diethylamhleethexyphenol in droxydiethylaminoacetanilide in 20 ccs. of acetone and 50 s of chloroform is ad T Xture is eft 0.01 mole of triethylamine is added, whereafter the overmght at and is then Worked p as in EXamPIe mixture is left overnight at 0 C. After washing with 16 h Y h 15 8 0f the crystalline henlylpeniellhnwater, sodium bicarbonate solution and water, the sof -(fl- )P y ester-Citrate With a D lution is dried over MgSO and then evaporated in vacu- Y 9 715 UJmg- The substance decomposes 011 um The residue is dissolved in anhydrous ethanol and heatmg to a temperature of the equivalent amount of hydrogen chloride in ethanol Example. 18 is added. On addition of ether, the hydrochloride is precipitated in amorphous form By re-prectpitatlon To a of g of the Sodlum Salt of from methanol-ether, the hydrochloride is obtained in g g g g g g g g i i'j i i g 10 o porp men en.ccs.oeycorocrystalline form the melting Pomt bemg 70 carbonate The mixture is stirred at 0 C. for 1 hour.

Then, 26.0 g. of p-hydroxybenzoic acid-diethylaminoethyl ester are added, whereafter the reaction mixture is left 'for 12 hours at 0 C. The precipitated sodium chloride is filtered off, and the solution of 25.0 g. of citric acid 'ester is obtained with melting point 141-42 C.

Iii :nronohydrate in 250 cos. of acetone is added .to the filtrate. Thereby, the citrate of thebenzylpenicillin ester of p-hydroxybenzoic acid-diethylaminoethyl ester crystallizes out. The yieldis .75 g. .orr85% .of the theoretical. The purity is 695 I. U./mg. andthemelting point is 100 C. (dec.).

Example 19 Toa solution of 0.02 mole of the mixed anhydride of benzylpenicillin and ethylcarbonic acid in-methylene chloride are added 4.9 g. of 2-(diethylaminomethyl)thiophenol. After standing for them, the mixture iswashed with a saturated solution of sodium bicarbonate. The methylene chloride phase is dried over magnesium sulhate and evaporated to a small volume. On addition of petrol ether, a syrup is precipitated whichcrystallizes on standing. By re-precipita'tion'fromether-petrol ether, pure benzylpenicillin Z-(diethylaminomethyl) thiophenyl and (a) =+177 '(in acetone).

Example 20 To 4.35 g. of the triethylamine salt dissolved in 30 ccs. of dry methylene 1.085 g. of ethyl chlorocarbonate at minutes, a mixture amino)thiophenolhydrochloride and 0.79 g. of pyridinein 20 ccs. of methylene chloride is added. After standing for 2 hours at 0 C., be mixture is washed with an aqueous solution of sodium bicarbonate. The methylene chloride phase is dried (MgSO and evaporated in vacuum to a syrup.

of benzylpenicillin chloride areadded C. After This is dissolved in 50 ccs. of isopropanol, and the solution is titrated with hydrogen chloride in ethanol. On addition of ether, benzylpenicillin-4- (diethylaminoacetamino)thiophenyl ester-hydrochloride is obtained as an amorphous, hygroscopic powder.

Analogous thiosalicylic acid-diethylaminoethyl ester gives 'benzy1penicillin-2-(carbo-[i-diethylaminoethoxy)thiophenyl ester-hydrochloride in a yield of 70% of the theoretical. The melting point is 135-36 C.

We claim:

1. Esters of penicillin with phenols having a basic substituent, said esters being represented by the formula:

PenC 0 0 where PenCO represents penicillin with hydroxyl removed from the carbonyl group; where Y is 'alkylene of not more than 4 carbon atoms in a straight chain, the total of 2.76 g. of 4-(diethylaminoacet- "12 number of carbon atoms in Y not exceeding .12; and where .-R and R are alkyl groups of not more than 4 carbonatoms each.

2. Esters of penicillin with thiophenols having a basic substituent, .said esters 'being represented by the formula:

PenG 0S wherePenCO represents penicillin with hydroxyl removed from the carboxylgroup; where Y is alkyleneof not more than 4 carbon'atoms ina straight chain, the total number of carbon atoms in .Y not exceeding 12', and where R and R areallcyl groups of not more than 4 carbon atoms each. 1

3. Esters of penicillin with phenols having a basic substituent, said esters being represented by the formula:

CHz-CH:

/-CH2 GET-CH1 where PenCO represents penicillin with hydroxyl removed from the carboxyl group; and where Y is alkylene of not- 6. Benzylpenicillin 4 (e dimethylaminoethy1)- phenyl ester.

7. Benzylpenicillinl-(fi-piperidinoethyl)-phenyl ester.

References Cited in the fiie of this patent UNITED STATES PATENTS 2,594,031 Fredericksen et al Nov. 9.1954 OTHER REFERENCES Carpenter: J. Am. Chem. Soc., vol. (1948), pp. 

1. ESTERS OF PENICILLIN WITH PHENOLS HAVING A BASIC SUBSTITUENT, SAID ESTERS BEING REPRESENTED BY THE FORMULA: 